Quantitative Systems Pharmacology and Machine Learning: A Match Made in Heaven or Hell?

As pharmaceutical development moves from early-stage in vitro experimentation to later in vivo and subsequent clinical trials, data and knowledge are acquired across multiple time and length scales, from the subcellular to whole patient cohort scale. Realizing the potential of this data for informing decision making in pharmaceutical development requires the individual and combined application of machine learning (ML) and mechanistic multiscale mathematical modeling approaches. Here we outline how these two approaches, both individually and in tandem, can be applied at different stages of the drug discovery and development pipeline to inform decision making compound development. The importance of discerning between knowledge and data are highlighted in informing the initial use of ML or mechanistic quantitative systems pharmacology (QSP) models. We discuss the application of sensitivity and structural identifiability analyses of QSP models in informing future experimental studies to which ML may be applied, as well as how ML approaches can be used to inform mechanistic model development. Relevant literature studies are highlighted and we close by discussing caveats regarding the application of each approach in an age of constant data acquisition. SIGNIFICANCE STATEMENT: We consider when best to apply machine learning (ML) and mechanistic quantitative systems pharmacology (QSP) approaches in the context of the drug discovery and development pipeline. We discuss the importance of prior knowledge and data available for the system of interest and how this informs the individual and combined application of ML and QSP approaches at each stage of the pipeline.

A mathematical model of the role of aggregation in sonic hedgehog signalling.

Effective regulation of the sonic hedgehog (Shh) signalling pathway is essential for normal development in a wide variety of species. Correct Shh signalling requires the formation of Shh aggregates on the surface of producing cells. Shh aggregates subsequently diffuse away and are recognised in receiving cells located elsewhere in the developing embryo. Various mechanisms have been postulated regarding how these aggregates form and what their precise role is in the overall signalling process. To understand the role of these mechanisms in the overall signalling process, we formulate and analyse a mathematical model of Shh aggregation using nonlinear ordinary differential equations. We consider Shh aggregate formation to comprise of multimerisation, association with heparan sulfate proteoglycans (HSPG) and binding with lipoproteins. We show that the size distribution of the Shh aggregates formed on the producing cell surface resembles an exponential distribution, a result in agreement with experimental data. A detailed sensitivity analysis of our model reveals that this exponential distribution is robust to parameter changes, and subsequently, also to variations in the processes by which Shh is recruited by HSPGs and lipoproteins. The work demonstrates the time taken for different sized Shh aggregates to form and the important role this likely plays in Shh diffusion.

Tamarix efficiency in salt excretion and physiological tolerance to salt-induced stress in South Africa.

This study, investigated the salt excretion efficiency and the level of the physiological response to salt-induced stresses between the native and exotic Tamarix species as well as their hybrids (Tamarix chinensis × Tamarix ramosissima and Tamarix chinensis × Tamarix usneoides). Ten potted plants from each of the five taxa were exposed to salt at a concentration of 3% (w/w) (180 mM) for 3 weeks. Measurements of electro-conductivity (EC), physiological parameters such as stomatal conductance, chlorophyll fluorescence, and water pressure and plant growth were taken from salt-treated and control plants. The EC in the exotic T. chinensis significantly increased by >30% compared with all other Tamarix taxa, suggesting that it is the most effective taxon for phytoremediation. Although there was no significant difference in plant growth between T. chinensis and T. usneoides, they both showed a significantly greater plant growth than the other taxa. However, the plant physiological parameters indicated that T. usneoides was less stressed by the salt exposure than the T. chinensis and the others. Thus, considering the T. usneoides greater tolerance to salt-induced and/water stresses and the strict environmental regulations of planting exotic Tamarix, the native Tamarix remains the preferred plant of choice for phytoremediation in South Africa.

Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation.

A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5- epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 µM against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damage upregulation that subsequently induces apoptosis.

Effects of contaminants of emerging concern on Myzus persicae (Sulzer, Hemiptera: Aphididae) biology and on their host plant, Capsicum annuum.

Many countries are utilizing reclaimed wastewater for agriculture as water demands due to drought, rising temperatures, and expanding human populations. Unfortunately, wastewater often contains biologically active, pseudopersistant pharmaceuticals, even after treatment. Runoff from agriculture and effluent from wastewater treatment plants also contribute high concentrations of pharmaceuticals to the environment. This study assessed the effects of common pharmaceuticals on an agricultural pest, the aphid Myzus persicae (Sulzer, Hemiptera: Aphididae). Second instar nymphs were transferred to bell peppers (Capsicum annuum) that were grown hydroponically. Treatment plants were spiked with contaminants of emerging concern (CECs) at environmentally relevant concentrations found in reclaimed wastewater. M. persicae displayed no differences in population growth or microbial community differences due to chemical treatments. Plants, however, displayed significant growth reduction in antibiotic and mixture treatments, specifically in wet root masses. Antibiotic treatment masses were significantly reduced in the total and root wet masses. Mixture treatments displayed an overall reduction in plant root wet mass. Our results suggest that the use of reclaimed wastewater for crop irrigation would not affect aphid populations, but could hinder or delay crop production.

Estimation of bladder contractility from intravesical pressure-volume measurements.

AIMS: To describe parameters from urodynamic pressure recordings that describe urinary bladder contractility through the use of principles of muscle mechanics. METHODS: Subtracted detrusor pressure and voided flow were recorded from patients undergoing filling cystometry. The isovolumetric increase of detrusor pressure, P, of a voluntary bladder contraction before voiding was used to generate a plot of (dP/dt)/P versus P. Extrapolation of the plot to the y-axis and the x-axis generated a contractility parameter, vCE (the maximum rate of pressure development) and the maximum isovolumetric pressure, P0 , respectively. Similar curves were obtained in ex vivo pig bladders with different concentrations of the inotropic agent carbachol and shown in a supplement. RESULTS: Values of vCE , but not P0 , diminished with age in female subjects. vCE was most significantly associated with the 20-80% duration of isovolumetric contraction t20-80 ; and a weaker association with maximum flow rate and BCI in women. P0 was not associated with any urodynamic variable in women, but in men was with t20-80 and isovolumetric pressure indices. CONCLUSIONS: The rate of isovolumetric subtracted detrusor pressure (t20-80 ) increase shows a very significant association with indices of bladder contractility as derived from a derived force-velocity curve. We propose that t20-80 is a detrusor contractility parameter (DCP). Neurourol. Urodynam. 36:1009-1014, 2017. © 2016 Wiley Periodicals, Inc.

Inhibition of protein tyrosine phosphatase (PTP1B) and α-glucosidase by geranylated flavonoids from Paulownia tomentosa.

Protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase are important targets to treat obesity and diabetes, due to their deep correlation with insulin and leptin signalling, and glucose regulation. The methanol extract of Paulownia tomentosa fruits showed potent inhibition against both enzymes. Purification of this extract led to eight geranylated flavonoids (1-8) displaying dual inhibition of PTP1B and α-glucosidase. The isolated compounds were identified as flavanones (1-5) and dihydroflavonols (6-8). Inhibitory potencies of these compounds varied accordingly, but most of the compounds were highly effective against PTP1B (IC50 = 1.9-8.2 µM) than α-glucosidase (IC50 = 2.2-78.9 µM). Mimulone (1) was the most effective against PTP1B with IC50 = 1.9 µM, whereas 6-geranyl-3,3',5,5',7-pentahydroxy-4'-methoxyflavane (8) displayed potent inhibition against α-glucosidase (IC50 = 2.2 µM). All inhibitors showed mixed type Ι inhibition toward PTP1B, and were noncompetitive inhibitors of α-glucosidase. This mixed type behavior against PTP1B was fully demonstrated by showing a decrease in Vmax, an increase of Km, and Kik/Kiv ratio ranging between 2.66 and 3.69.

Neurogenic lower urinary tract dysfunction: Clinical management recommendations of the Neurologic Incontinence committee of the fifth International Consultation on Incontinence 2013.

BACKGROUND: Evidence-based guidelines for the management of neurological disease and lower urinary tract dysfunction have been produced by the International Consultations on Incontinence (ICI). These are comprehensive guidelines, and were developed to have world-wide relevance. AIMS: To update clinical management of neurogenic bladder dysfunction from the recommendations of the fourth ICI, 2009. MATERIALS AND METHODS: A series of evidence reviews and updates were performed by members of the working group. The resulting guidelines were presented at the 2012 meeting of the European Association of Urology for consultation, and consequently amended to deliver evidence-based conclusions and recommendations in 2013. RESULTS: The current review is a synthesis of the conclusions and recommendations, including the algorithms for initial and specialized management of neurogenic lower urinary tract dysfunction. The pathophysiology is categorized according to the nature of onset of neurological disease and the part(s) of the nervous system affected. Assessment requires clinical evaluation, general investigations, and specialized testing. Treatment primarily focuses on ensuring safety of the patient and optimizing quality of life. Symptom management covers conservative and interventional measures to aid urine storage and bladder emptying, along with containment of incontinence. A multidisciplinary approach to management is essential. DISCUSSION: The review offers a pragmatic review of management in the context of complex pathophysiology and varied evidence base. Neurourol. Urodynam. 35:657-665, 2016. © 2016 Wiley Periodicals, Inc.

Classification of stress urinary incontinence.

INTRODUCTION: The relevant terminology for stress urinary incontinence (SUI) is affected by the context, namely the clinical assessment (the symptom of SUI elicited on history taking and the sign of SUI observed during examination) or diagnostic investigations (urodynamic stress incontinence). In some cases, SUI may only be observed after the reduction in coexistent prolapse (occult SUI). Classifying SUI often relies on distinguishing between intrinsic sphincter deficiency (ISD), and urethral malposition or hypermobility, although this potentially an over-simplification. REVIEW: Classification systems have been derived based on clinical assessment and diagnostic testing, notably videourodynamics. Modern developments in imaging technology may allow other techniques such as ultrasound to offer additional basis for future developments in classification. Other urodynamic approaches include urethral pressure profilometry and Valsalva leak point pressure; these may offer indicators of thresholds below which ISD is more likely to explain SUI, but they are not generally accepted in routine practice. CONCLUSIONS: While SUI classification is potentially relevant to treatment selection, evidence for influence on management outcome is limited. Generating a high-quality evidence base for treatment selection on these criteria is problematic, particularly due to the range of confounding factors. In practice, the modern practitioner relies on various tools to form an opinion on some key aspects, using the findings to derive a treatment strategy. Accordingly, there remains a need to confirm how a classification of SUI translates into treatment selection and better outcomes.

Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits.

Tribulus terrestris fruits are well known for their usage in pharmaceutical preparations and food supplements. The methanol extract of T. terrestris fruits showed potent inhibition against the papain-like protease (PLpro), an essential proteolylic enzyme for protection to pathogenic virus and bacteria. Subsequent bioactivity-guided fractionation of this extract led to six cinnamic amides (1-6) and ferulic acid (7). Compound 6 emerged as new compound possessing the very rare carbinolamide motif. These compounds (1-7) were evaluated for severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro inhibitory activity to identify their potencies and kinetic behavior. Compounds (1-6) displayed significant inhibitory activity with IC50 values in the range 15.8-70.1 µM. The new cinnamic amide 6 was found to be most potent inhibitor with an IC50 of 15.8 µM. In kinetic studies, all inhibitors exhibited mixed type inhibition. Furthermore, the most active PLpro inhibitors (1-6) were proven to be present in the native fruits in high quantities by HPLC chromatogram and liquid chromatography with diode array detection and electrospray ionization mass spectrometry (LC-DAD-ESI/MS).

Advancing community-based research with urban American Indian populations: multidisciplinary perspectives.

The US has witnessed significant growth among urban American Indian (AI) populations in recent decades, and concerns have been raised that these populations face equal or greater degrees of disadvantage than their reservation counterparts. Surprisingly little urban AI research or community work has been documented in the literature, and even less has been written about the influences of urban settings on community-based work with these populations. Given the deep commitments of community psychology to empowering disadvantaged groups and understanding the impact of contextual factors on the lives of individuals and groups, community psychologists are well suited to fill these gaps in the literature. Toward informing such efforts, this work offers multidisciplinary insights from distinct idiographic accounts of community-based behavioral health research with urban AI populations. Accounts are offered by three researchers and one urban AI community organization staff member, and particular attention is given to issues of community heterogeneity, geography, membership, and collaboration. Each first-person account provides "lessons learned" from the urban context in which the research occurred. Together, these accounts suggest several important areas of consideration in research with urban AIs, some of which also seem relevant to reservation-based work. Finally, the potential role of research as a tool of empowerment for urban AI populations is emphasized, suggesting future research attend to the intersections of identity, sense of community, and empowerment in urban AI populations.

Z-REX uncovers a bifurcation in function of Keap1 paralogs.

Studying electrophile signaling is marred by difficulties in parsing changes in pathway flux attributable to on-target, vis-à-vis off-target, modifications. By combining bolus dosing, knockdown, and Z-REX-a tool investigating on-target/on-pathway electrophile signaling, we document that electrophile labeling of one zebrafish-Keap1-paralog (zKeap1b) stimulates Nrf2- driven antioxidant response (AR) signaling (like the human-ortholog). Conversely, zKeap1a is a dominant-negative regulator of electrophile-promoted Nrf2-signaling, and itself is nonpermissive for electrophile-induced Nrf2-upregulation. This behavior is recapitulated in human cells: (1) zKeap1b-expressing cells are permissive for augmented AR-signaling through reduced zKeap1b-Nrf2 binding following whole-cell electrophile treatment; (2) zKeap1a-expressing cells are non-permissive for AR-upregulation, as zKeap1a-Nrf2 binding capacity remains unaltered upon whole-cell electrophile exposure; (3) 1:1 ZKeap1a:zKeap1b-co-expressing cells show no Nrf2-release from the Keap1-complex following whole-cell electrophile administration, rendering these cells unable to upregulate AR. We identified a zKeap1a-specific point-mutation (C273I) responsible for zKeap1a's behavior during electrophilic stress. Human-Keap1(C273I), of known diminished Nrf2-regulatory capacity, dominantly muted electrophile-induced Nrf2-signaling. These studies highlight divergent and interdependent electrophile signaling behaviors, despite conserved electrophile sensing.

The Association Between Constipation and Lower Urinary Tract Symptoms in Parous Middle-Aged Women: A Prospective Cohort Study.

Objective: To examine the prospective association between constipation and risk of developing lower urinary tract symptoms (LUTS) in parous middle-aged women. Materials and Methods: The study uses data from 3,729 women from the Avon Longitudinal Study of Parents and Children who provided self-reports of medication intake for constipation at two time points (Baseline): 2001-2003 and 2003-2005. Women with LUTS at baseline were excluded. After 10 years of follow-up, women provided self-reports of LUTS using an adapted version of the International Consultation on Incontinence Questionnaire on Female LUTS. LUTS were categorized according to International Continence Society definitions as stress urinary incontinence (UI), urgency UI, mixed UI, nocturia, increased daytime frequency, urgency, hesitancy, and intermittency. LUTS were considered present if symptoms were reported to occur at least "sometimes" for all subtypes, except for increased daytime frequency (≥9 times) and nocturia (≥2 times nightly). Results: At follow-up, the prevalence of any LUTS was 40%. Women (mean age 43.3 years, standard deviation 0.5), who took medication for constipation at either time point had increased risks of urgency (adjusted relative risks [RRs] = 1.35; 95% confidence interval [CI] 1.04-1.95) and hesitancy (adjusted RR = 1.72; 95% CI 1.04-3.01) compared with women who reported not using medication for constipation at either time point. The risk of urgency (adjusted RR = 1.94; 95% CI 1.15-3.29) and hesitancy (adjusted RR = 1.78; 95% CI 1.03-4.19) was greater for women who reported taking medication for constipation at both time points. There was no evidence that constipation was associated with stress UI, urgency UI, mixed UI, nocturia, increased daytime frequency, and intermittency. Conclusion: Constipation is prospectively associated with an increased risk of urgency and hesitancy among parous middle-aged women. If further research finds evidence that this association is causal, this implies that women should seek treatment to alleviate constipation to reduce their consequent risk of developing these LUTS.

Presence of the esp gene in Enterococcus faecium derived from oropharyngeal microbiota of haematology patients.

OBJECTIVES: Antibiotic use and immunocompromised status in haematology patients have been shown to determine the constituents of commensal microbiota with highly increased resistance, including vancomycin resistant enterococci. We compared the carriage of virulence factor genes and the capacity for biofilm formation in vancomycin resistant enterococci (VRE) originating from the oropharyngeal and stool cultures of haematology patients. DESIGN: PCR tests were used to investigate the presence of genes encoding pathogenicity factors (esp and hyl) in VRE isolates. The genotype of vancomycin resistance was investigated by multiplex PCR tests for vanA and vanB genes. PFGE typing was conducted to exclude the duplicate isolates. RESULTS: Of 3310 pharyngeal swabs taken from inpatients at a clinic for haematology, Enterococcus species were recovered in 6.46%. All VRE investigated were identified as Enterococcus faecium and were highly vancomycin resistant. VanA genotype was confirmed in all. In the group of oropharyngeal carriers (n = 8 patients), 15 strains were recovered from oropharyngeal specimens and PFGE typing revealed 5 types and 3 subtypes. Identical types of VRE in the oropharynx and stool cultures were found in three patients from this group. In the group of stool carriers (n = 24 patients) VRE were obtained from stools only and placed in 21 macro-restriction patterns. The esp gene was more common in VRE isolated from the oropharynx than in isolates from stools (p = 0.014). Results were not significant when we compared the presence of hyl genes in oropharyngeal isolates with those from stool cultures (p = 0.66) or when we investigated the association between esp and hyl gene carriage and capability of biofilm formation in non-repeated VRE. CONCLUSIONS: In the present study, isolation of VRE from the oropharynx in haematology patients was associated with esp gene carriage. Further research is needed to investigate the clinical and long-term effects of this finding.

Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing.

Treatment expectations but not preference affect outcome in a trial of CBT and exercise for pain.

Background: Patients' beliefs and attitudes toward a treatment can affect treatment response. In unblinded trials this can affect outcomes. Aims: The aim of this analysis was to examine the association between treatment preference and expectation and outcome in a trial of pain treatments. Methods: In a randomized trial (ISRCTN67013851) of four treatments for chronic widespread pain, participants were asked which they would prefer and what improvement they expect from each. The proportion of participants reporting positive health outcomes at three time points after treatment were compared between those matched or unmatched with their preference and between those with and without expectation for improvement. Odds ratios were calculated adjusted for baseline characteristics associated with preference and expectation. Results: Four hundred forty-two participants were recruited to the trial (69.5% female). The proportion reporting positive outcomes among participants matched to their preference compared to those unmatched was 33.3% vs. 34.4% at the end of treatment (adjusted odds ratio [aOR] = 0.80, 95% confidence interval [CI], 0.44-1.46), 34.4% vs. 29.0% at 3 months (aOR = 1.23, 95% CI, 0.67-2.26), and 34.8% vs. 30.3% at 2 years (aOR = 1.31, 95% CI, 0.70-2.46). The proportion of participants reporting positive outcomes among those expecting improvement compared to those not expecting improvement was 36.6% vs. 15.0% at the end of treatment (aOR = 2.03, 95% CI, 1.07-3.85), 34.1% vs. 13.2% at 3 months (aOR = 2.31, 95% CI, 1.22-4.38), and 32.8% vs. 19.1% at 2 years (aOR = 1.16, 95% CI, 0.67-2.36). Conclusions: Treatment preference had no clear effect on outcomes, but expectation did. These results could inform future approaches to management, and researchers assessing treatments should take into account this expectation effect.

Contexte: Les croyances et les attitudes des patients à l'égard d'un traitement peuvent influencer la réponse à ce traitement. Dans des essais sans insu, il peut y avoir un effet sur les résultats. Buts: Le but de cette analyse était d'étudier le lien entre les préférences et les attentes à l'égard du traitement, et le résultat obtenu dans un essai portant sur les traitements de la douleur. Méthodes: Dans un essai randomisé (ISRCTN67013851) portant sur quatre traitements pour la douleur chronique généralisée, on a demandé aux participants quelle était leur préférence quant au traitement, ainsi que l'amélioration qu'ils attendaient de chacun de ces traitements. Une comparaison de la proportion de participants ayant rapporté des résultats positifs sur leur santé à trois moments différents après le traitement a été effectuée entre ceux qui ont reçu le traitement qu'ils préféraient et ceux qui ont reçu un traitement autre que celui qu'ils préféraient, ainsi qu'entre ceux qui s'attendaient à une amélioration et ceux qui n'avaient pas de telles attentes. Les rapports de cotes ont été calculés et ajustés selon les caractéristiques de départ en ce qui concerne la préférence et les attentes. Résultats: Le nombre de participants recrutés pour cet essai était de 442 (69,5 % de femmes). La proportion de participants ayant rapporté un résultat positif parmi ceux qui ont reçu le traitement qu'ils préféraient comparativement à ceux qui ont reçu un traitement autre que celui qu'ils préféraient était de 33,3 % comparativement à 34,4 % à la fin du traitement (RC ajusté 0,80, 95 % IC 0,44-1,46); de 34,4 % comparativement à 29,0 % après trois mois (RCa 1,23, 0,67 ­ 2,26) et de 34,8 % comparativement à 30,3 % après deux ans (RCa 1,31, 0,70 ­ 2,46). La proportion de participants ayant rapporté des résultats positifs parmi ceux qui s'attendaient à une amélioration comparativement à ceux qui n'avaient pas de telles attentes était de 36,6 % comparativement à 15,0 % à la fin du traitement (RCa 2,03, 1,07-3,85), de 34,1 % comparativement à 13,2 % après trois mois (RCa 2,31, 1,22-4,38), et de 32,8 % comparativement à 19,1 % après deux ans (RCa 1,16, 0,67-2,36).Conclusions: La préférence en matière de traitement n'a pas eu d'effet clair sur les résultats, contrairement aux attentes. Ces résultats pourraient inspirer les approches futures en matière de prise en charge, tandis que les chercheurs qui évaluent des traitements devraient tenir compte de l'effet des attentes.

ß-TrCP1 Is a Vacillatory Regulator of Wnt Signaling.

Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the ß-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits ß-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between ß-catenin N terminus and ß-TrCP1 (an antagonist of both Nrf2 and ß-catenin), and independent of binding between Nrf2 and ß-TrCP1. Intriguingly, ß-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of ß-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis.

Annual direct and indirect costs attributable to nocturia in Germany, Sweden, and the UK.

OBJECTIVE: Our aim was to estimate the prevalence-based cost of illness imposed by nocturia (≥2 nocturnal voids per night) in Germany, Sweden, and the UK in an average year. METHODS: Information obtained from a systematic review of published literature and clinicians was used to construct an algorithm depicting the management of nocturia in these three countries. This enabled an estimation of (1) annual levels of healthcare resource use, (2) annual cost of healthcare resource use, and (3) annual societal cost arising from presenteeism and absenteeism attributable to nocturia in each country. RESULTS: In an average year, there are an estimated 12.5, 1.2, and 8.6 million patients ≥20 years of age with nocturia in Germany, Sweden, and the UK, respectively. In an average year in each country, respectively, these patients were estimated to have 13.8, 1.4, and 10.0 million visits to a family practitioner or specialist, ~91,000, 9000, and 63,000 hospital admissions attributable to nocturia and 216,000, 19,000, and 130,000 subjects were estimated to incur a fracture resulting from nocturia. The annual direct cost of healthcare resource use attributable to managing nocturia was estimated to be approximately €2.32 billion in Germany, 5.11 billion kr (€0.54 billion) in Sweden, and £1.35 billion (€1.77 billion) in the UK. The annual indirect societal cost arising from both presenteeism and absenteeism was estimated to be approximately €20.76 billion in Germany and 19.65 billion kr (€2.10 billion) in Sweden. In addition, in the UK, the annual indirect cost due to absenteeism was an estimated £4.32 billion (€5.64 billion). CONCLUSIONS: Nocturia appears to impose a substantial socioeconomic burden in all three countries. Clinical and economic benefits could accrue from an increased awareness of the impact that nocturia imposes on patients, health services, and society as a whole.